Two projects involving structure determinations of proteins that are drug design targets are described. The proteins are the microsomal triglyceride transfer protein (MTP), and human cytomegalovirus (HCMV) protease. Each of these projects involves the use of three-dimensional structural information to aid in the design of new therapeutic agents. In each case, the goal is to inhibit a novel protein target. Each of these structures projects presents special challenges that require the use of a high brilliance synchrotron radiation source for data collection. In the case of MTP, limits of resolution of native and derivative data from crystals of this large protein (150 kDa) must be extended to solve the structure. In the case of HCMV protease, where two useful derivatives have been identified, limits of resolution, which are favorable along c*, must be extended in the rest of the sphere of reflection in order to produce an interpretable map.